Sulfone salts deriving from 2,5-dihydroxy benzene monosulfonic and 2,5-dihydroxy benzene disulfonic acids

ABSTRACT

Sulfone salts deriving from 2,5-dihydroxy benzene monosulfonic and 2,5-dihydroxy benzene disulfonic acids have the general formula:   WHEREIN R is an aryl, alkylaryl or aralkyl radical, and B represents a cation of an alkali metal, an alkaline-earth meta of ammonium, of an amine, substituted or un-substituted, open chained or cyclic, and are remarkable for their hemostatic, hypocholesteremic, hypotriglycidemic and hypolipidemic activity.

United States Patent [191 Esteve-Subirana 1 SULFONE SALTS DERIVING FROM2,5-DI11IYDROXY BENZENE MONOSULFONIC AND 2,5-DIHYDROXY BENZENEDISULFONIC ACIDS [75] Inventor: Antonio Esteve-Subirana,

Barcelona, Spain [73] Assignee: Laboratories del Dr. Esteve S.A.,

Geneva, Switzerland [22] Filed: May 14, 1973 [21] Appl. No.1 359,772

[52] US. Cl..... 260/512 C, 260/512 R, 260/501.21, 260/501.l9, 424/315,424/316 OTHER PUBLICATIONS Stecher et al., The Merck Index," 8th ed, p.1178 (1968).

[ 1 Mar. 25, 1975 Prinmry Examiner-Bernard Helfin AssistantExaminer-Nicky Chan Attorney, Agent, or FirmHume. Clement, Brinks,Willian, Olds & Cook, Ltd.

[57 ABSTRACT Sulfone salts deriving from 2,5-dihydroxy benzenemonosulfonic and 2,5-dihydroxy benzene disulfonic acids have the generalformula:

OH OH S 02R S 03.081; CELLOgS CalLOsS S 03R OH OH I II -SO2R (III)wherein R is an aryl, alkylaryl or aralkyl radical, and B represents acation of an alkali metal, an alkalineearth meta of ammonium, of anamine, substituted or un-substituted, open chained or cyclic, and areremarkable for their hemostatic, hypocholesteremic, hypotriglycidemicand hypolipidemic activity.

5 Claims, N0 Drawings 2,5-DIHYDROXY BENZENE MONOSULFONIC ANTS2,5-DIHYDROXY BENZENE DISULFONIC ACIDS This invention is directed tonovel sulfone salts deriving from 2,5-dihydroxybenzene monosulfonic and2,5- dihydroxybenzene disulfonic acids, as well as a process forpreparing them. These compounds have the general formulae:

wherein R is an aryl, alkylaryl or aralkyl radical, and B represents acation of an alkali metal, alkaline-earth metal, ammonium or of asubstituted or unsubstituted amine, e.g. alkanolamines, alkylandarylamines, cyclic amines, etc.

The process according to the invention for preparing compounds havingthe general formulas l, II and III is characterized in that a salt ofquinone monoor disulfonic acid having the formula:

is reacted with an acid of formula: RSO H where, when R, is hydrogen, Rcan be hydrogen or SO;,.B, and when R, is SO -,.B, R is hydrogen. R hasthe meaning almve-defined.

The starting quinones are obtained from the corresponding hydroquinonesby oxidizing with nitric acid in aqueous or alcoholic medium, asdescribed in the following Examples,

This process is based upon the HINSBERG reaction for forming sulfones byaddition of sulfinic acids to quinones. In this process, one uses, forthe first time, quinonesulfonic acids which, by reacting withsubstituted sulfinic acid, produce sulfones of hydroquinone sulfonicacids, no examples whereof are known, at the present date, in thechemical litterature.

Preferably the reaction is carried out in aqueous or aqueous-alcoholicmedium, and generally using an alkali metal salt of quinone sulfonicacid. ln this way the reaction is successfully carried out in ahomogenous medium. and the alkali metal salt of the sulfone ofhydroquinone sulfonic acid is readily obtained. The great stability andwater solubility of the produce obtained allows it to be separated fromthe solution previously rendered colourless with active charcoal, byevaporating to dryness, using preferably vacuum distillation.

The residual oil solid is treated with ethanol and the desired productprecipitates in a substantially white state.

The following Examples illustrate the invention.

EXAMPLE 1 Preparation of the potassium salt of2,5-dihydroxy-3,6-disulfon-4'-methyl-diphenylsulfone:

A slurry of l 1 gr of p-toluenesulfinic acid in l00 ml of water isplaced in a 250 ml Erlenmeyer. To this slurry 25 gr of potassiump-quinone-2,5-disulfonate are added, and stirring is maintained for 4hours. The water is vacuum-evaporated, and the residual oil is poured on200 ml of ethanol. A precipitate is formed, which is collected on afilter, and is washed with ethanol and ether. 29 gr of the2,5-dihydroxy-3,6-disulfo-4'-methyldiphenylsulfone potassium salt areobtained. The infrared spectrum recorded in a KBr pellet gives maxima atthe following frequencies: 1410, 1220, 1150, 1020, and 655 cm,

EXAMPLE 2 2,5-dihydroxy-4-sulfo-4'-methyldiphenylsulfone sodium salt l60gr of p-toluensulfinic acid in 1000 ml of water are slurried in a 3liter beaker provided with strong mechanical stirring means, and 208 grof sodium quinone sulfonate are added gradually. The stirring ismaintained during four hours, and the water is vacuumevaporated. Theresidue is treated with ethanol, and it is then collected on a filterand washed with ethanol and ethyl ether. 277 gr of the sodium salt of2,5- dihydroxy-4-sulfo-4-methyldiphenylsulfone are obtained. Theinfra-red spectrum recorded in a KBr pellet gives maxima at thefollowing frequencies: 3220, I425, l225, 1200, 1120, 1040, 890. and 670cm.

EXAMPLE 3 2,5-dihdroxy-4,6-disulfo-4-methyldiphenylsulfone potassiumsalt 22 gr ofp-toluenesulfinic acid in 200 ml of water are slurried in a500 ml beaker provided with strong mechanical stirring means, and 50 grof potassium p-quinone-Z,o-disulfonate are added gradually. Stirring iscontinued for 5 hours, and then the water is vacuum evaporated. Theresulting product is treated with ethanol and ethyl ether and 60 gr ofthe potassium salt of2,5-dihdroxy-4,6-disull'o-4'-methyldiphenylsull'one are obtained. Theinfrared spectrum recorded with a KBr pellet gives maxima at thefollowing frequencies: 3440, 3220, 1415, 1220, 1200, 1090, 1040, 890,820, 705. and 660 cm".

The starting materials used in these Examples can be obtained asfollows: Sodium quinone sulfonate:

ml of concentrated nitric acid and 90 ml of absolute ethanol are placedin a 2 liter beaker provided with mechanical stirring means. 300 gr ofsodium 2,5- dihydroxy benzene sulfonate are added gradually, and moreethanol is added as required by the reaction, i.e. up to 300 ml.

Stirring is continued for half an hour, and at the end of this periodthe precipitate formed is collected on a filter, and it is washed withethanol and ethyl ether.

260 gr of sodium p-quinone sulfonate are obtained. Potassium quinonesulfonate:

20 ml of concentrated nitric acid and 20 ml of water are placed in a-dihydroxybenzene ml vessel. 30 gr of potassium 2,5-dihdrosybenzonedisulfonate are added gradually. It is stirred for half an hour, andfiltered, and the solid is washed with ethanol and ethyl ether. 25 gr ofpotassium p-quinone sulfonate are obtained.

2,5-dihydroxy-4-sulfo-4'-methyldiphenyl sulfone calcium salt 5 gr of thesodium salt of 2,5-dihdroxy-4-sulfo-4- methyldiphenyl sulfone aredissolved in 100 ml of dis-' tilled water, and are passed through acolumn containing 50 gr of strong acid cation resin (LAB I, Merck). Thestrongly acid solution obtained is neutralized with calcium carbonate,it is filtered, and evaporated to dryness. The resulting solid isdissolved in alcohol and concentrated. Ethyl ether is added and 4.4 grof calcium salt of 2,5-dihydroxy-4-sulfo-4-methy1 diphenyl sulfone areobtained.

The infrared spectrum recorded with a KBr pellet gives maxima at thefollowing frequencies: 3410, 1630, 1210, 1150, 1045, and 810 cm.

EXAMPLE 5 2,5-dihydroxy-4-sulfo-4-methyl diphenyl sulfone. diethylaminesalt:

5 gr of the sodium salt of 2,5-dihydroxy-4-sulfo-4'- methyldiphenylzsulfone are dissolved in 100 ml of distilled water, and arepassed through a column containing 50 gr of strong acid cation resin(LAB 1, Merck).

The strongly acid solution obtained is neutralized with diethyl amine,filtered, and evaporated to dryness. The residue obtained isdissolved-in alcohol, and precipitated with ethyl ether. 3.9 gr ofdiethylamine salt of the 2,5-dihydroxy-4-sulfo-4-methy1 diphenyl sulfoneare obtained, having a melting point of 275C (dec.). The infraredspectrum recorded with a KBr pellet gives maxima at the followingfrequencies: 3320, 1420, 1300, 1190, 1140, 1100, 1045, 805, and 655 cm".

The compounds of general formulae 1, II, AND 111 possess veryinteresting pharmacodynamical properties, such as hemostatic, and theyprovide a powerful hypocholesterolemic, hypoglyeedemic, and hypolipidicaction.

The pharmacodynamical properties of the compounds in accordance with theinvention are illustrated by those of the sodium salt of2,5-dihydroxy-4-sulfo-4- methyl diphenyl sulfone prepared in Example 2.

1. Acute toxicity in mice and rats 18 to gr albino mice.

100 to 150 gr Sprague-Dawley rats.

The LD was determined by the Reed and Muench method.

methyldiphenyl sulfone, administered intraveinously, produces a loweringof the ABT in the rabbit, determined by ROSKAMs technique, modified byLA- PORTE, (Chemotherapia, 3,62, 1961). The effects of the product areobserved as soon as the 2.5 micromoles/kg does is given. which, 1 hourafter administration, reduces the ABT by 14 With increasing doses, theeffect increases progressively to a maximum of 50 The effect of theproduct remains constant at least until 4 hours after administration;thus, for example, 10 micromoles/kg cause a reduction of the ABT of 31.5in the 1st hour, 33 in the second hour, and 32 in the 4th hour.

3. Hypolipemic action on the rat 'fiiiraufitbr sodium salt of2,5-dihydroxy-4-sulfo- 4'-methyldiphenyl sulfone administered is 2mmoles/kg, orally. The letter P means probability.

TABLE 11 Triton 2,5-dihydroxy-4-sulfo-4'- Tritonmethyldiphenylsulfone/salt sodium Total cholesterol mg ml of plasma240.7 i 10.1 210.0 8.7

A 72 with respect to Triton 13 Free cholesterol mg 7r ml of plasma 61.5i 3.9 48.9 i 1.8

A with respect to Triton 20 7t 1 Triton 2,5-dihydro- Tritonxy-4-sulfo-4'-methyldiphenyl-sulfone/salt s 'um P 0.005 P O.(l0l

Triglycerides mg 71 ml of plasma 888.2 i 44.9 669.] i 25.7

A "/1 with respect to Triton 25 '/1 'l'otal lipids mg /1 ml 01 plasma2833.8 1- 164.9 2243 i 97.0

A 71 with respect to Triton 21 71 The proposed close for humans is l to2 gr per day. The preferred pharmaceutical forms are tablets andcapsules, containing 250 mg or 500 mg of active compound of formula I,II or 111 per unit.

Examfile of formula per tablet (500 mg dose) 6 l claim: consisting of analkali metal cation. an equivalent 1. A compound of formula: of analkaline earth metal cation, the ammonium H ion.

? 2. The compound of claim 1 in which cat is an alkali soz 5 metalcation. Camis 3. The compound ofclaim 1 in which cat is a sodium cation.4. The compound of claim 1 in which cat is an alkaline earth metalcation. wherein the sulfo group SO;;.CE1 S Selected from 5. The compoundof claim 1 in which cat is the calthose in the meta and para position tothe sulfone Cium Cation group, and wherein cat is selected from thegroup UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No,Dated Ma-Tch 25,

Antonio Esteve suhirana Inventor-(s) It is certified that error appearsin the above-identified patent and that said Letters Patent are herebycorrected as shown below:

Abstract, Formula II, "80 R" should read H 50 R Abstract, -6 lines fromend: "B" should read Cat Column 1, lines after 10, Formula II: "80 R"should read Column 1, line 25, "B" should read H Cat Column 1 line 43,"-80 B" should read -SO 'Cat Column 1, line 44, "SO B" should read -SO-Cat Column 1, line 55 "litterature" should read literature Column 1line 63, "produce" should read product Column 2 line 66 "dihydrosy"should read dihydroxy Column 4, line 3, "does" should read dose Claim 1,next to last line, before "the ammonium," insert and Signed and Scaledthis Third Day of May 1977 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner ofPatenlsand Trademarks

1. A COMPOUND OF FORMULA
 2. The compound of claim 1 in which cat is analkali metal cation.
 3. The compound of claim 1 in which cat is a sodiumcation.
 4. The compound of claim 1 in which cat is an alkaline earthmetal cation.
 5. The compound of claim 1 in which cat is the calciumcation.